ArticleProceedings of the National Academy of Sciences of the United States of America2020
Allosteric control of hemoglobin S fiber formation by oxygen and its relation to the pathophysiology of sickle cell disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 57 citations in OpenAlex.
- In vivo measurement of RBC survival in patients with sickle cell disease before or after hematopoietic stem cell transplantation.Blood advances · 2024Trial
- Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial.Nature medicine · 2022Trial
- Review
- Review
- Mechanotransduction mechanisms in human erythrocytes: Fundamental physiology and clinical significance.Channels (Austin, Tex.) · 2025Review
- Exploring the Hemoglobin T to R2 Path Using Gaussian Elastic Network Correlation Map Distance.Proteins · 2025Article
- Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor.ACS medicinal chemistry letters · 2025Article
- Hyperactive deoxy-PIEZO1 shapes the circulatory life cycle of irreversibly sickled cells.Biophysical journal · 2025Article
- The brief life-story of irreversibly sickled cells.Biophysical journal · 2025Article
- Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.Cell stem cell · 2025Article
- Therapeutic potential of the latest oxygen affinity-modifying agent, GBT021601, for treating sickle cell disease is questionable.British journal of haematology · 2024Article
- Transcriptional regulators of fetal hemoglobin.Hematology, transfusion and cell therapy · 2024Review
- CRISPR/Cas9 in the treatment of sickle cell disease (SCD) and its comparison with traditional treatment approaches: a review.Annals of medicine and surgery (2012) · 2024Review
- A parameterized two-domain thermodynamic model explains diverse mutational effects on protein allostery.eLife · 2024Article
- A parametrized two-domain thermodynamic model explains diverse mutational effects on protein allostery.bioRxiv : the preprint server for biology · 2024Article
- Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease.Scientific reports · 2024Article
- Therapeutics for sickle cell disease intravascular hemolysis.Frontiers in physiology · 2024Review
- Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment.Haematologica · 2023Article
- Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling.Nature communications · 2023Article
- Phenotypic screening of the ReFRAME drug repurposing library to discover new drugs for treating sickle cell disease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
The pathology of sickle cell disease is caused by polymerization of the abnormal hemoglobin S upon deoxygenation in the tissues to form fibers in red cells, causing them to deform and occlude the circulation. Drugs that allosterically shift the quaternary equilibrium from the polymerizing T quaternary structure to the nonpolymerizing R quaternary structure are now being developed. Here we update our understanding on the allosteric control of fiber formation at equilibrium by showing how the simplest extension of the classic quaternary two-state allosteric model of Monod, Wyman, and Changeux to include tertiary conformational changes provides a better quantitative description. We also show that if fiber formation is at equilibrium in vivo, the vast majority of cells in most tissues would contain fibers, indicating that it is unlikely that the disease would be survivable once the nonpolymerizing fetal hemoglobin has been replaced by adult hemoglobin S at about 1 y after birth. Calculations of sickling times, based on a recently discovered universal relation between the delay time prior to fiber formation and supersaturation, show that in vivo fiber formation is very far from equilibrium. Our analysis indicates that patients survive because the delay period allows the majority of cells to escape the small vessels of the tissues before fibers form. The enormous sensitivity of the duration of the delay period to intracellular hemoglobin composition also explains why sickle trait, the heterozygous condition, and the compound heterozygous condition of hemoglobin S with pancellular hereditary persistence of fetal hemoglobin are both relatively benign conditions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.